Chemical resolution of chiral (.+-.)-secondary amines with optically active acids is the classical method to prepare the optical antipodes of these amines. Many examples are cited in the text by Paul Newman "Optical Resolution for Chemical Compounds: Vol. 1: Amines and Related Compounds", Opt. Resolution Inf. Center, Manhattan College, Riverdale, N.Y. 10471 (1976). Chemical resolution is used in the total synthesis of (-)-emetine, (-)-salsolidine, and (+)-N-norreticuline required for a total synthesis of opium alkaloids. Chemical resolution is a critical step in the synthesis of optically active amines which, if used as drugs, have to be optically pure. Analytical methods to measure optical purity were developed by reacting optically active secondary amines with commercially available R-(+)- or S-(-)-methylbenzylisocyanate, or naphthylethyl analogs, and were frequently used. In this reaction, illustrated in Scheme 2 optically active methylbenzylureas (-)-B and (-)-C are formed which can be separated by chromatographic methods, such as HPLC, TLC, or column chromatography on silica gel or aluminum oxide, or simply by crystallization from solvents, water, or solvent mixtures. The composition of the reaction mixture can be analyzed by .sup.1 H-NMR techniques, and optical purity, or the degree of optical impurity be calculated. This in principle elegant method for separating secondary amines in form of methylbenzylurea derivatives, is lacking synthetic utility, since these ureas could not be converted into optically active amines.
Secondary amines biologically active as one of the two optical isomers are represented by (-)-emetine (Merck Index 3523), a useful amebicide, and (+)-mecamylamine, a useful antihypertensive drug as the racemate (Merck Index No. 5595). A separation of racemic normorphinans into optical isomers affords the (-)-enantiomer which can be converted into the narcotic analgetic drug dromoran (Merck Index No. 5297), and the (+)-isomer which can be converted into the antitussive agent dextromethorphan (Merck Index No. 8009), and is described by Hellerbach et al. in "Synthetic Analgesics, Part II (A) Morphinans." Secondary amines can be converted into primary amines or tertiary amines by well established chemical reactions shown below. A successful resolution of secondary amines, therefore, in principle also includes the preparation of optically active primary and tertiary amines.
Such methods include formation of a Schiff base from a primary amine I with an aldehyde and reduction to the secondary amine by borohydrides or catalytically. The Nbenzyl substituted secondary amine II is a secondary amine which, can after successful resolution, be reconverted into the primary amine I by catalytic debenzylation, or further alkylated to a tertiary amine III, also obtainable from I by direct alkylation, or from II by reaction with chloroformates and reduction of the carbamate with LAH.
A practical method for resolving enantiomeric mixtures of secondary amines, therefore, provides an entry into optically active primary amines exemplified with (+)-amphetamine called dextroamphetamine (Merck Index No. 2918), an appetite suppressant, or tertiary amines such as (-)-physostigmine (Merck Index No. 7267), an anticholinesterase agent useful in treating Alzheimers disease. ##STR1##